The Future of Managing Pain: Novel Treatments & Reformulations

By: Jody Lutz

Reading Time: 7 minutes

Date: 01/02/2019

As the opioid misuse and overdose epidemic impacts communities across America and has sweeping global implications, practitioners are looking to the future of pain management and the novel treatment options that may be on the horizon.

Drug trends related to pain management focus on efficacy and patient safety, but with renewed attention to abuse deterrent formulations and side effect profiles. Novel agents as well as reformulations of older, industry standard products are being studied. 



The Food and Drug Administration announced on August 29, 2018 that it intends to withdraw its existing analgesic guidance for developing new pain drugs and will issue new comprehensive guidance in 2019.

The ADA concisely summarizes the new guidance documents:

  • Regarding non-opioid alternatives,  the guidance “will set forth the FDA’s current thinking on how sponsors can demonstrate a clinically meaningful reduction in the use of opioid pain medications when used for acute pain." 
  • Charging drug makers with assessing the benefits and risks when new opioid pain drugs are put into development. “This will include an updated framework for evaluating the risks associated with intentional or illicit misuse or abuse of drugs.”
  • Developing extended-release local anesthetics, which can serve as an alternative to the systemic use of oral opioid drugs. “This guidance will address the clinical pharmacology, the proper evaluation of safety and efficacy, and the types of studies that may support approval of these products.”
  • Assisting sponsors with the development of new non-opioid pain medications for chronic pain that can provide therapeutic alternatives to the use of opioids.

Additionally, the FDA is encouraging the development of prescription opioids with abuse-deterrent formulations (ADFs) to help combat the opioid crisis. The agency recognizes that abuse-deterrent opioids are not abuse- or addiction-proof but are a step toward products that may help reduce abuse.

Defining Abuse-Deterrent Formulations

As defined by the FDA:

"Abuse-deterrent formulations target the known or expected routes of abuse, such as crushing in order to snort or dissolving in order to inject, for the specific opioid drug substance."

The science of abuse-deterrents and technology used to create them are relatively new and rapidly evolving. To support advancements in this area, the FDA is aiding drug manufacturers, especially through the regulatory process.

So Where is Drug Development Heading?

Several reformulations of existing products have attempted to become commercially available.

After experiencing success in early trials, Pain Therapeutics's Oxytrex failed their phase III trial. Oxytrex is an Oxycodone plus ultra-low dose Naltrexone, investigational drug that showed promise in initial trials to minimize physical dependence while providing analgesic efficacy. Ultimately, the product was not approved by the FDA.

In 2018, the company’s next attempt at an Oxycodone reformulation was denied FDA approval. Remoxy ER was a new formulation of oral oxycodone designed to deter abuse but still provide 12 hours of pain relief. The formulation had a thick, sticky, high viscosity, hydrophobic, gel formulation that prevents possible drug abusers from cutting, grating, or dividing the drug into smaller particle sizes. It is also resistant to being modified to be injected.

John Carrol summarized on the endpts website, “A panel of outside experts turned thumbs down on the application by a vote of 14 to 3 as the agency remains vigilant over any pain remedies that could prove vulnerable to abuse.”

However not all reformulations met such a decisive end. In 2016 Troxyca ER, manufactured by Pfizer was approved by the FDA. Troxyca ER is an oxycodone hydrochloride and naltrexone hydrochloride extended release capsule for oral use. It is indicated for the management of pain severe enough to require daily, around the clock, long-term opioid treatment and for which alternative treatments are inadequate. 

Capsaicin - The Red Hot Chili Pepper

Capsaicin, the active compound in chili peppers has been touted for its pain-relieving properties since its discovery in the early 1800’s. This natural compound binds to pain receptors. Capsaicin is currently available over the counter in a cream format or as a dietary supplement. 

On the horizon, the potential for a capsaicin therapy injected directly into the knee joint is being studied, CNTX-4975 developed by Centrexion Therapeutics. The company boasts their STRATI (Synthetic TRans cApsaicin ulTra-pure Injection) technology is a highly potent, ultra-pure synthetic form of trans-capsaicin that is injected directly into the site of pain. 

Cannabis Providing Medical Advancement

We have covered the legalization of marijuana in several states on our blog as well as the use of medical marijuana. But this summer the U.S. Food and Drug Administration approved Epidiolex (cannabidiol) [CBD] oral solution for the treatment of seizures associated with two rare and severe forms of epilepsy, Lennox-Gastaut syndrome and Dravet syndrome, in patients two years of age and older. This is the first FDA-approved drug that contains a purified drug substance derived from marijuana. 

“This is an important medical advance. But it’s also important to note that this is not an approval of marijuana or all of its components. This is the approval of one specific CBD medication for a specific use. And it was based on well-controlled clinical trials evaluating the use of this compound in the treatment of a specific condition,” FDA commissioner Scott Gottlieb, MD, said in a statement.

The Pain News Network adds, “While Epidiolex is only approved for the treatment of Lennox-Gastaut syndrome and Dravet syndrome, doctors will presumably be able to prescribe it “off label” for other conditions such as chronic pain.”

Epidiolex is manufactured by GW Pharmaceuticals, who also produces Nabiximols marketed as Sativex, an oral spray that contains tetrahydrocannabinol (THC) and cannabidiol (CBD).

Sativex was the first cannabis-based medicine to be approved in the UK. First being licensed for the treatment for MS-related spasticity when a person has shown inadequate response to other symptomatic treatments or found their side effects intolerable. Sativex has also been studied for its effects on a number of MS related symptoms including "effective long term treatment of neuropathic pain in Multiple Scherosis (MS)."

Sativex has also been approved in several other European countries as well as Canada, Australia, and New Zealand for the treatment of muscle spasticity caused by multiple sclerosis. In Israel, Sativex is also approved for the treatment of pain and chronic non-cancer pain.

A New Generation of Pain Medications and What is On The Horizon 

Multiple sites, including Science Daily ran stories this September touting the researchers from Charité -- Universitätsmedizin Berlin and the Zuse Institute Berlin. Together they have developed a new generation of pain medications.

The researchers used computer simulations to develop new opioids that will only work at sites affected by injury or inflammation. These drugs can prevent the occurrence of brain- and gut-related side effects typically associated with conventional opioids and have been shown to be successful in preclinical studies. Results from this research have been published in Pain and Scientific Reports.

The National Institute of Health (NIH) is also investing in new therapeutic options. The plan, called HEAL (Helping to End Addiction Long-term), includes new grants for 2018 and 2019 for academic groups and companies to fund the discovery of new drug targets and devices to safely treat pain ($20 million for 2018). The plan also creates new partnerships between the NIH, FDA, and companies to share data and assets on new non-addictive pain therapies that might be just sitting on shelves ($2.1 million for 2018), discover new biomarkers for pain ($1.2 million), and build a clinical trials network focused on conducting phase 2 trials of some of those shared assets ($1.8 million). Learn more here.

Finding A Non-Addictive Pain Killer

New non-opioid alternatives are being studied in primates, with the support of the National Institute on Drug Abuse, scientists at Wake Forest School of Medicine have been working to find a non-addictive pain killer.

Research is ongoing for the compound known as AT-121 which suppresses oxycodone’s reinforcing effects and exerted morphine-like analgesic effects in nonhuman primates. AT-121 treatment did not induce side effects commonly associated with opioids, such as respiratory depression, abuse potential, opioid-induced hyperalgesia, and physical dependence. 

"In our study, we found AT-121 to be safe and non-addictive, as well as an effective pain medication," said Mei-Chuan Ko, Ph.D., professor of physiology and pharmacology at the School of Medicine, part of Wake Forest Baptist Medical Center. "In addition, this compound also was effective at blocking abuse potential of prescription opioids, much like buprenorphine does for heroin, so we hope it could be used to treat pain and opioid abuse."

All of these novel treatments we've explored here are important to watch as communities continue to combat the opioid crisis. The future is full of potential in both reformulations and new technology. Investment is being made both by private and public institutions to better treat pain conditions and address the shortcomings of traditional opioid therapies.

In the meantime, you can turn to our blog for updates as we continue to report on developments of interest to you, your practice, and your patients.


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